Idiopathic pulmonary fibrosis is a rare and progressive, fatal disease for which there is no effective treatment. Dysregulated wound healing by subsets of fibrogenic lung fibroblasts leads to fibrosis in idiopathic pulmonary fibrosis. TGF-( is a key regulator of wound healing responses and its action is critical for fibrogenic progression. TGF-( must be activated from its latent state to affect these responses. Our data show that one of the differential characteristics of fibroblast subsets is the capacity to activate latent TGF-( in response to injury. The presence of the GPI-anchored protein, Thy-1, on lung fibroblasts limits the ability to activate TGF-(. These data suggest that Thy-1 is a biological response modifier which limits TGF-( activation. Thy-1 (-) fibroblasts express higher levels of the latent TGF-( binding protein 4 (LTBP-4) when stimulated with bleomycin than do Thy-1 (+) cells, consistent with the increased TGF-( activity in the lungs of LTBP-4 hypomorphic mice. Thy-1 (-) LTBP-4 hypomorphic lung fibroblasts fail to activate latent TGF-( in response to bleomycin, suggesting that LTBP-4 is necessary for the ability of Thy-1 (-) cells to respond. Since TGF-( activity is critical to the fibrogenic progression of pulmonary fibrosis, the capacity of interstitial fibroblasts to activate latent TGF-( could be a key determinant of either benign resolution of lung injury or the development of fibrotic complications. We hypothesize that the ability of pulmonary fibroblasts to activate latent TGF-( in response to stimulation is critical to fibrogenic progression following lung injury. Thus fibroblasts with attenuated TGF-( activation would favor limited wound healing responses, whereas, fibroblasts that exhibit robust TGF-( activation in response to injury would favor fibrogenic responses. The overall goal of this proposal is to determine how modulating TGF-( activation by lung fibroblasts affects progression of pulmonary fibrosis. We will use a novel strategy that employs a modified adenovirus and a fibroblast-specific promoter to drive fibroblast specific transgene expression of Thy-1 and LTBP-4 in vivo to test the effects of fibroblast-specific expression of these proteins on fibrogenic progression in a mouse model of bleomycin-induced pulmonary fibrosis. We propose the following aims: Specific Aim 1: To test the hypothesis that fibroblast-specific over-expression of Thy-1 protects from bleomycin-induced pulmonary fibrosis by limiting TGF-( activation and to determine if expression of constitutively active TGF-( abrogates the potential protective effects of Thy-1 overexpression; Specific Aim 2: To test the hypothesis that fibroblast expression of LTBP-4 is necessary for activation of latent TGF-( in vitro and whether LTBP-4 abrogates Thy-1 protection in vivo. These studies will provide new insights into how lung fibroblast subpopulations determine fibrogenic progression and potentially identify new therapeutic approaches to treat idiopathic pulmonary fibrosis. [unreadable] [unreadable] [unreadable] [unreadable]